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Resume La frequence du diabete de type 1 (DT1) augmente chez l’enfant et l’adolescent, en particulier avant l’âge de 5 ans. Les progres dans le traitement par l’insuline et l’education therapeutique ont permis de reduire le risque des complications microvasculaires. D’autres perspectives dans le traitement, mais aussi la prevention du DT1, rendent indispensables sa prise en charge par des equipes pediatriques pluridisciplinaires specialisees.

Resume Le diabete de type 1 est de plus en plus frequent avant l’âge de 15 ans, et plus encore avant l’âge de 5 ans. La frequence de l’acidocetose au moment du diagnostic chez l’enfant et l’adolescent est tres elevee en France, avec une importante morbidite et plusieurs deces chaque annee. Le retard au diagnostic peut etre evite par l’information des professionnels et du grand public, sur les signes revelateurs du diabete et sur l’urgence du diagnostic, en particulier chez les plus jeunes enfants. Le role des medecins generalistes est crucial pour cette prevention.

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen.

Resume L’objectif de cette etude etait d’evaluer, au cours de la premiere annee suivant une campagne nationale d’information, l’effet sur la frequence et la severite de l’acidocetose au moment du diagnostic de diabete de type 1 (DT1) chez l’enfant et l’adolescent. Les donnees suivantes ont ete colligees pendant deux annees consecutives chez les jeunes de moins de 15 ans ayant un DT1 debutant dans 146 services de pediatrie : âge, sexe, duree des symptomes, parcours du patient, signes cliniques et biologiques, antecedents familiaux de DT1. L’acidocetose etait definie par un pH p = 0,08), exclusivement du fait d’une diminution des acidocetoses severes, de 14,8 a 11,4 % ( p = 0,01). Dans les groupes d’âge 0–5 ans et 5–10 ans, la baisse relative de la frequence de l’acidocetose a ete respectivement de 13 % et 15 %, et celle des formes severes de 23 % et 41 %. Chez les enfants adresses a l’hopital par un pediatre ou venus a l’initiative de la famille, elle a ete respectivement de 34 et 7 %, et celle des formes severes de 39 et 32 %. Aucun changement n’a ete observe pour les jeunes de 10–15 ans et pour ceux qui ont ete adresses par un medecin generaliste. En analyse multivariee, une frequence plus elevee de l’acidocetose etait associee avec le jeune âge de l’enfant (

Resume Quel que soit l’âge de l’enfant, le but de l’insulinotherapie sera un remplacement aussi physiologique que possible de l’insuline et un equilibre glycemique optimal. L’objectif sera d’avoir sur 24 heures des niveaux d’insuline correspondant aux besoins de base et des quantites plus elevees au moment des repas. Les insulines utilisees chez l’enfant sont les analogues rapides et lents de l’insuline qui permettent un meilleur controle de la glycemie postprandiale et qui ont permis de diminuer le risque d’hypoglycemie. La repartition de la dose d’insuline sur la journee va varier d’un individu a l’autre ainsi que dans le temps chez un meme individu, et les doses devront etre adaptees a l’equilibre glycemique et regulierement reevaluees. L’insuline sera administree a l’aide d’un materiel adapte aux enfants (stylos ou seringues a insuline ou pompe a insuline). Enfin, quel que soit le schema de traitement choisi, il doit s’appuyer sur une education adaptee a l’âge, a la maturite et aux besoins individuels de l’enfant et de sa famille.

PREDICTIVE (an ongoing multinational observational study) provides an opportunity to explore the impact of insulin detemir use in routine clinical practice. Here, we report on long-term (52-week) data from a French cohort of patients (n=1772), comprising 643 with type 1 diabetes and 1129 with type 2 diabetes.Patients were prescribed insulin detemir at their physician's discretion and assessed at various visits (baseline, 12 weeks, 26 weeks and 52 weeks). The primary endpoint was the frequency of serious adverse drug reactions, including major hypoglycaemia. Secondary endpoints included minor and nocturnal hypoglycaemia, glycaemic control (HbA(1c), fasting blood glucose and variability of fasting blood glucose) and weight change.The incidence of serious adverse drug reactions was low throughout the study, seen in 10 patients with type 1 diabetes (14 events, 1.6%) and seven with type 2 diabetes (seven events, 0.6%). In both type 1 and type 2 diabetes cohorts, the overall minor and nocturnal hypoglycaemic events were reduced from baseline (P0.001), with no clinically significant changes in weight from baseline to endpoint. After 52 weeks of treatment with insulin detemir, glycaemic control improved, with reductions in: HbA(1c), by -0.6% and -0.8% in type 1 and type 2 diabetes patients, respectively; fasting blood glucose, by -1.4mmol/L and -1.9mmol/L respectively; and FBG variability, by -0.8mmol/L and -0.3mmol/L, respectively (P0.0001 for all).Patients treated with insulin detemir in a clinical healthcare setting improved their glycaemic control with no increases in hypoglycaemia, adverse events or weight compared with baseline.

Resume Objectifs Le but de cette etude etait d'evaluer les resultats du depistage de la thyroidite et de la maladie cœliaque, dans une population d'enfants et d'adolescents ayant un diabete de type 1, et de comparer l'apparition des anticorps specifiques de ces 2 maladies en fonction de l'âge. Patients et methodes La population etudiee comprenait 370 enfants et adolescents, 179 filles et 191 garcons, âges de 13,8 ± 4,4 ans et ayant un diabete depuis 7,1 ± 3,8 ans. Le depistage de la thyroidite auto-immune a ete realise a l'aide des anticorps antimicrosomes et antithyroglobuline, a un rythme moyen de 3 tests par patient (1 tous les 2 ans), et complete par les dosages de TSH et FT4 ; celui de la maladie cœliaque par les anticorps antigliadine (± antiendomysium), a un rythme moyen de 2 tests par patient, le diagnostic etant confirme par la biopsie duodenojejunale. L'evolution des anticorps antithyroide en fonction de l'âge a ete etudiee selon une approche de type « analyse de donnees censurees ». Resultats Les anticorps antithyroide ont ete trouves chez 42 patients (11,4 %), dont 9 etaient traites pour une hypothyroidie et 1 pour une maladie de Basedow, et ceux de la maladie cœliaque chez 9 patients (3,2 % des patients testes). La frequence cumulee des anticorps antithyroide augmentait regulierement avec l'âge et etait significativement plus elevee chez les filles, atteignant vers l'âge de 18 ans 28 % chez les filles et 12 % chez les garcons. Consequence de cette evolution, les anticorps antithyroide etaient frequemment trouves au moment du diagnostic de diabete quand celui-ci apparaissait apres 10 ans, alors qu'ils se positivaient souvent secondairement quand le diabete debutait avant 10 ans. Les anticorps de la maladie cœliaque apparaissaient beaucoup plus tot et etaient presents au moment du diagnostic de diabete ou lors du premier test de depistage. Conclusion La frequence des anticorps antithyroide augmente avec l'âge et est tres elevee chez les filles. Le rythme du depistage doit etre adapte a l'evolution des anticorps en fonction de l'âge, qui est tres differente dans la thyroidite et dans la maladie cœliaque.

Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The 2 subunits of the K(+)(ATP) channel are encoded by either the sulfonylurea receptor gene (SUR1 or ABCC8) or the inward-rectifying potassium channel gene (KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [(18)F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus.

When energy intake is restricted in mammals, there are neuroendocrine adjustments in the secretion of reproductive and metabolic hormones to reallocate energy for vital functions. In the present study, we investigated whether there were differences in the luteinising hormone (LH), growth hormone (GH) and cortisol responses to a 48-h fast in adult gonad-intact male and female rhesus macaques. In both male and female macaques, blood glucose levels were significantly lower in fasted than in control studies, and levels were higher in males than in females. Male rhesus monkeys had significantly lower (P < 0.01) mean serum LH levels after a 48-h fast than under fed conditions and this was attributable primarily to a decrease in the amount of LH released during each secretory episode. In fasted females, serum LH levels were significantly greater (P < 0.05) than during the fed conditions but no differences were found in pulse amplitude or in the number of pulses. Almost twice as many GH pulses were observed in both males and females during fasting but there was no difference in either mean serum GH levels or pulse amplitude between control and fasted studies. A typical diurnal profile in cortisol levels was observed in both sexes and both experimental conditions. Under control conditions, male macaques released less cortisol than females, and although fasting increased mean cortisol levels in both males and females, only the males shown a significant rise over levels observed in control studies. The changes in plasma LH and cortisol levels in fasted rhesus macaques are similar to those observed in humans and suggest that gonadotrophin and corticotrophin secretion are more resistant to short-term energy deprivation in female than in male primates.

We describe here a clonal approach for efficient and robust construction of recombinant adenoviral genomes that holds certain advantages over existing approaches. Transgenes of interest are cloned into a small, conditionally replicating plasmid containing the left end of a recombinant adenoviral genome, encompassing pIX coding regions. Transformation of this plasmid into recombination-competent Escherichia coli bearing a plasmid containing the right end of a recombinant adenoviral genome, commencing from pIX coding regions, yields a stable co-integrated plasmid encoding a full adenoviral genome, by virtue of shared homology in pIX coding regions contained in both plasmids. The recombination process yielding the full adenoviral plasmid requires only one step, and always results in the formation of only the desired recombinant adenoviral genome. Thus, no screening is required to identify the correct plasmid encoding the desired recombinant adenoviral genome. In addition, the plasmid encoding the right-hand side of the adenoviral genome is itself incapable of producing contaminating adenovirus. We have successfully employed this approach to generate over 200 recombinant adenoviruses, obtaining only the desired recombinant adenoviral species each time. The process is amenable to medium-to-high-throughput parallel construction of adenoviral genomes, and as such should aid efforts aimed towards high-throughput functional annotation of therapeutic gene targets, which aim to leverage the benefits of adenoviruses as gene delivery and expression vectors.

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen.

The aim of the study was to evaluate, after the first year of a national information campaign, the effect on the frequency and severity of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) in children and adolescents in France. The following data were collected during a 2-year period in people younger than 15 years of age at diagnosis of T1D, in 146 pediatric centers: age, sex, duration of symptoms, patient's previous care, clinical and biological signs, and family history of T1D. DKA was defined as pH7.30 or bicarbonate15mmol/L, severe DKA as pH7.10 or bicarbonate5mmol/L. During the 2nd year, an information campaign targeting health professionals and families was launched with the objective of reducing the time to diagnosis. Data were compared between the year before the campaign (year 0) and the first year of the campaign (year 1). The number of new cases of T1D was 1299 for year 0 and 1247 for year 1. Between year 0 and year 1, the rate of DKA decreased from 43.9% to 40.5% (P=0.08), exclusively due to the decrease of severe DKA from 14.8 to 11.4% (P=0.01). In the 0- to 5-year-old and 5- to 10-year-old age groups, the relative decrease in the rate of DKA was 13% and 15%, and 23% and 41% for severe DKA, respectively. In patients referred to the hospital by a pediatrician or who came at the family's initiative, the decrease was 34% and 7%, and 39% and 32% for severe DKA, respectively. No change was observed in the 10- to 15-year-old group or in those children who were referred by a general practitioner. In multivariate analyses, a higher DKA rate was associated with the young age of the child (5 years), being hospitalized at the parents' initiative rather than being referred by a doctor, and the absence of a family history of T1D. A higher rate of severe DKA was associated with these last two factors but not with the child's age. The frequency of DKA at diagnosis of type 1 diabetes remains high in children and adolescents, but the first year of an information campaign decreased it. The results have also helped better define the strategy and targets of the continuing prevention campaign, to more efficiently reduce the morbidity and mortality of T1D at diagnosis in children and adolescents in France.

Objective:To evaluate the relationships between asthma and type and incidence of psychiatric problems in a pediatric population.Methods:A series of 93 children and adolescents with asthma presenting during a 1-year period to a pediatric pneumology and allergy service was studied. Their psychopathological problems were compared with those of 93 children with insulin-dependent diabetes mellitus (IDDM). Various questionnaires were completed by the patients: the Child Depression Inventory (CDI), the State-Trait Anxiety Inventory for Children (STAIC), and the Coopersmith Self-Esteem Inventory (SEI). Their parents were administered the Child Behavior Checklist (CBCL). The patients were examined using the revised Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-R).Results:There were more symptoms in the asthma group than in the IDDM group, as indicated by total CBCL scores, internalization and externalization CBCL subscores, and the STAIC scores. Asthma was often associated with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) psychiatric disorders. We found 30 anxiety disorders, 5 affective disorders, and 6 disruptive behaviour disorders. Asthmatic children did not seem to be more depressed than the IDDM group, and their self-esteem, overall, was good. However, the asthma subgroup presenting with psychiatric disorders had poorer self-esteem and social competence. Adolescents did not seem to suffer more psychiatric disturbances than did younger patients. Girls did not suffer more psychiatric disturbances than did boys.Conclusion:Asthma appears to be associated both with higher overall incidence of psychiatric problems than in IDDM and with particular categories of psychiatric problems. In particular, the problems include anxiety disorders, internalizing symptoms, and disruptive behaviours.

BACKGROUND: Neonatal hyperinsulinemic hypoglycemia is often resistant to medical therapy and is often treated with near-total pancreatectomy. However, the pancreatic lesions may be focal and treatable by partial pancreatic resection. METHODS: We studied 52 neonates with hyperinsulinism who were treated surgically. The type and location of the pancreatic lesions were determined by preoperative pancreatic catheterization and intraoperative histologic studies. Partial pancreatectomy was performed in infants with focal lesions, and near-total pancreatectomy was performed in those with diffuse lesions. The postoperative outcome was determined by measurements of plasma glucose and glycosylated hemoglobin and by oral glucose-tolerance tests. RESULTS: Thirty neonates had diffuse beta-cell hyperfunction, and 22 had focal adenomatous islet-cell hyperplasia. Among the latter, the lesions were in the head of the pancreas in nine, the isthmus in three, the body in eight, and the tail in two. The clinical manifestations were similar in both groups. The infants with focal lesions had no symptoms of hypoglycemia and had normal preprandial and postprandial plasma glucose and glycosylated hemoglobin values and normal results on oral glucose-tolerance tests after partial pancreatectomy (performed in 19 of 22 neonates). By contrast, after near-total pancreatectomy, 13 of the patients with diffuse lesions had persistent hypoglycemia, type 1 diabetes mellitus developed in 8, and hyperglycemia developed in another 7; overall, only 2 patients with diffuse lesions had normal plasma glucose concentrations in the first year after surgery. CONCLUSIONS: Among neonates with hyperinsulinism, about half may have focal islet-cell hyperplasia that can be treated with partial pancreatectomy. These neonates can be identified through pancreatic catheterization and intraoperative histologic studies.

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.

Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of their direct involvement, the LOH may also unmask a recessive mutation leading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI. Thus, this somatic event which leads both to beta cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.

Sporadic persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a heterogeneous disorder characterized by profound hypoglycemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI) because management strategies differ significantly. 16 infants with sporadic PHHI resistant to diazoxide and who underwent pancreatectomy were investigated. Selective pancreatic venous sampling coupled with peroperative surgical examination and analysis of extemporaneous frozen sections allowed us to identify 10 cases with FoPHHI and 6 cases with DiPHHI. We show here that in cases of FoPHHI, but not those of DiPHHI, there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event is consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, we provide the first molecular explanation of the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia.

Resume Le diabete insulinodependant (DID) est souvent evoque comme facteur de risque des troubles psychopathologiques. L'objectif de ce travail est de montrer le type de troubles psychiatriques rencontres dans le suivi de ces patients et leurs relations avec l'equilibre metabolique, dans une population d'enfants et d'adolescents DID consultant en pedopsychiatrie. Patients et methode. - La population etudiee consiste en 57 sujets, 20 garcons et 37 filles, âges en moyenne de 14,7 ± 4,1 ans, dont le DID evolue en moyenne depuis 5,6 ± 4,3 ans. Ils ont ete suivis sur 1 an par le meme pedopsychiatre, avec une duree moyenne du suivi pedopsychiatrique de 22 mois. Ils ont ete evalues au cours d'entretiens cliniques repetes (en moyenne trois par sujet) et les troubles psychiatriques ont ete classes a l'aide des criteres du ⪡ Manuel diagnostique et statistique des troubles mentaux ⪢, 3 e edition revisee, DSM III-R. Resultants. - Les resultats font apparaitre la frequence des troubles emotionnels, 30 sujets presentant au moins un trouble anxieux et 17 un trouble de l'humeur ; 11 un etat depressif majeur et huit un trouble dysthymique. Les troubles anxieux les plus frequents etaient les troubles phobiques et l'hyperanxiete. Deux sujets presentaient une anorexie mentale, un presente une boulimie nerveuse et neuf un trouble des conduites alimentaires non specifie. Dix diagnostics de troubles perturbateurs du comportement ont ete portes, un d'abus de substances toxiques et 11 de troubles de l'adaptation. Sept sujets avaient une dyslexie-dysorthographie, trois un trouble d'acquisition de la coordination et trois un niveau intellectuel limite. Les facteurs familiaux sont apparus comme tres importants. Neuf sujets avaient un probleme parents-enfant, quatre un syndrome de rivalite fraternelle, et deux un trouble de l'attachement. Les problemes familiaux (conflits, divorce, difficultes economiques…) etaient rencontres dans 63 % des cas. Le pere ou la mere avait des troubles psychiatriques dans 24 cas (42 %). Les patients diabetiques ayant des troubles psychiatriques avaient un desequilibre metabolique (HbAlC = 9,9 ± 2,4 %) et dix sujets (18 %) avaient deja des complications somatiques. Certains troubles psychiatriques etaient significativement associes au desequilibre metabolique. Les plus forts desequilibres metaboliques etaient releves pour les troubles des conduites alimentaires. Les complications somatiques n'etaient associees qu'a la duree d'evolution du DID. Conclusions. - Ce travail montre la presence de troubles psychiatriques caracterises selon le DSM III-R dans le DID de l'enfant, surtout des troubles emotionnels, et leur association a un risque somatique accru, maximal pour les troubles des conduites alimentaires, mettant en evidence tout l'interet d'une collaboration diabetologue/pedopsychiatre. La prevalence exacte de ces problemes doit etre evaluee dans des enquetes epidemiologiques.

In all age groups, the aim of insulin treatment will be as close to physiological insulin replacement as possible in order to obtain optimum metabolic control. Rapid and long acting insulin analogs represent some improvement in the care of diabetes in children by improving glycaemic control and decreasing the occurrence of hypoglycaemia. Insulin dosage will be determined to allow appropriate insulin levels throughout the twenty-four hours to cover basal requirements and higher levels of insulin in an attempt to match the glycaemic effect of meals. The distribution of insulin dose across the days shows great individual variations and daily insulin dosage varies greatly between individuals end changes over time. Regardless of mode of insulin therapy, doses should be adapted based on the daily pattern of blood glucose and therefore require regular review and assessment. The device used for insulin administration must be adapted for paediatric patients. Whatever insulin regimen is chosen it must be supported by comprehensive education adapted for the age, maturity and individual needs of the child and family.

International audience; OBJECTIVES: This study aimed to evaluate the frequency of diabetic ketoacidosis (DKA) and its associated factors at the diagnosis of type 1 diabetes (T1D) in French children and adolescents prior to launching a public-health campaign of information to prevent DKA. PATIENTS AND METHODS: Over a 1-year period, 1299 youngsters (aged

We have previously shown that the phorbol ester, TPA, which activates protein kinase C, causes, in PC12 cells, a transcriptional activation of tyrosine hydroxylase (TH), the key enzyme in catecholamine synthesis. The study has now been extended to examine the processes that underlie this transcriptional stimulation and, in addition, to seek whether similar mechanisms are involved in long-term trans-synaptic induction of the TH gene in adrenal medullae of rats that have been given a single injection of reserpine. In both systems, it was found that the induction of c-fos gene transcription was associated with that of the TH gene but with different kinetics. The promoter of the TH gene contains (at position -207/-200) a sequence (TGATTCA) which differs from the consensus TRE or AP-1 site (TGACTCA) by one nucleotide. Experiments were carried out to investigate whether the AP-1 protein complex which is known to contain Fos and Jun binds to the putative TRE region of the TH promoter. In the gel shift assays, the nuclear protein extracts derived from TPA-treated PC12 cells and from AM of reserpine injected rats displayed a higher magnitude of binding to a 25-mer TRE-TH oligonucleotide as compared to controls. The results showed that the behaviour of TRE-TH was atypical in that two retarded complexes (A and B) were observed, which were displaced by specific competitors. Trans-activation experiments with plasmids TRE-TH/TK/CAT and -754/-19 TH/pUC18-CAT in PC12 cells showed an increase in CAT activity in response to TPA that correlates with the previously observed increase in TH transcriptional activity by TPA.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the effect of insulin deficiency on whole body glutamine kinetics, five young adults with type I (insulin-dependent) diabetes received 4-h primed continuous infusions of L-[1-13C]leucine and L-[2-15N]glutamine in the postabsorptive state after blood glucose had been clamped overnight at either a normoglycemic level (approximately 85 mg/dl) or a moderate hyperglycemic level (approximately 260 mg/dl) by means of an automated glucose control insulin infusion system. The hyperglycemic state was associated with a significant rise in leucine level [from 165 +/- 23 to 242 +/- 62 (SD) microM], appearance rate (from 125 +/- 11 to 142 +/- 17 mumol.kg-1.h-1), and oxidation (from 27 +/- 10 to 31 +/- 10 mumol.kg-1.h-1). In contrast, neither the plasma level nor the appearance rate of glutamine (333 +/- 51 vs. 318 +/- 58 mumol.kg-1.h-1) was affected. We conclude that insulin deficiency resulting in moderate hyperglycemia induces a 13% rise in whole body proteolysis and yet does not stimulate glutamine de novo synthesis, despite increased precursor availability.

Objectif Etudier l’evolution des schemas de traitement par l’insuline chez les enfants et les adolescents ayant un diabete de type 1, et leurs liaisons avec l’HbA1c. Patients et methodes L’etude a inclus 4 293 enfants et adolescents (âge: 12,9 ± 2,6 ans, plus d’un an de diabete), ayant participe aux sejours d’ete de l’Aide aux Jeunes Diabetiques (AJD) de 2009 a 2014. La distribution des differents schemas de traitement, et les liaisons entre Hb1Ac, schemas therapeutiques, connaissance du diabete (questionnaire AJD) et qualite de vie (Ingersoll et Marrero, version courte du Hvidoere Study Group) ont ete evaluees en fonction des annees. Resultats Le pourcentage de jeunes traites par la pompe a augmente jusqu’a environ 45 %, celui des schemas basal bolus s’est maintenu au-dessus de 40 %, alors que les autres schemas ont diminue de facon tres marquee. L’HbA1c a diminue de 0,014 % par an et le pourcentage d’HbA1c ≤ 7,5 % n’a pas augmente, sauf avec la pompe ; celui d’HbA1c > 9 % et > 10 % a diminue de plus de moitie et de facon plus marquee avec la pompe. L’HbA1c est significative-ment plus basse avec la pompe (8,12 ± 1,09 %) et 2-3 injections (8,18 ± 1,28 %) qu’avec le basal bolus (8,32 ± 1,33 %). L’HbA1c est correlee au niveau de connaissance du diabete chez les jeunes de plus de 14 ans, et fortement correlee aux scores de qualite de vie independamment de l’âge. Conclusion Le pourcentage des jeunes qui atteint l’objectif de 7,5 % d’HbA1c progresse peu, alors que le pourcentage de ceux qui sont les plus a risque de complications est en nette diminution. La distribution des HbA1cs evalue mieux l’equilibre glycemique d’une population que la moyenne ou le pourcentage de patients ayant atteint l’objectif. L’HbA1c est plus fortement liee a la qualite de vie qu’aux schemas therapeutiques et a la connaissance du diabete. Declaration d’interet Les auteurs declarent ne pas avoir d’interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

This study aimed at evaluating the screening of thyroïditis and coeliac disease, in a population of children and adolescents with type 1 diabetes, and at comparing the appearance of antibodies specific for these 2 diseases as a function of age.The study included 370 children and adolescents, 179 girls and 191 boys, aged 13.8 +/- 4.4 yr and with diabetes for 7.1 +/- 3.8 yr. Auto-immune thyroïditis was screened using antimicrosomal and antithyroglobulin auto-antibodies, at a mean rhythm of 3 tests per patient (1 every 2 yr), associated with dosages of TSH and FT4. Coeliac disease was screened using antigliadin (+/- antiendomysium) auto-antibodies, at a mean rhythm of 2 tests per patient, and was confirmed by duodenojejunal biopsy. Antithyroïd auto-antibodies were correlated with age following the "censured data analysis" type approach.Antithyroïd autoantibodies were found in 42 patients (11.4%), of whom 9 were treated for hypothyroïdism and 1 for Basedow disease, and coeliac disease autoantibodies were found in 9 patients (3.2% of tested patients). The cumulated frequency of antithyroïd auto-antibodies increased regularly with age and was significantly higher in girls, reaching 28% in girls and 12% in boys around 18 yr of age. As a consequence of this evolution, antithyroïd auto-antibodies were frequently found at the time of diagnosis of diabetes when it declared after 10 yr of age, while they often became positive secondarily when diabetes occurred before 10 yr of age. Coeliac disease specific auto-antibodies appeared much earlier and were found at the time of diagnosis of diabetes or at the first screening test.Antithyroïd autoantibodies are increasingly frequent with age in children with type 1 diabetes, and become very elevated in girls. The rhythm for screening should be adapted to this evolution of autoantibodies with age, which is very different between thyroïditis and coeliac disease.

Congenital hyperinsulinism (HI), the most important cause of hypoglycaemia in early infancy, is a heterogeneous disease with two types of histological lesions, focal and diffuse, with major consequences in terms of surgical approaches. In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessively inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism. Thus, dominant HI disorders always correspond to diffuse HI, where most hypoglycaemia occur in infancy, and are sensitive to medical treatment. Channel causes could be due to dominant negative mutation with one abnormality in channels composed of four Kir6.2 subunits and four SUR1 subunits, leading to a complete destruction of the channel structure or function, or due to haploinsufficiency with only one functional allele, leading to 50% of functional protein, which is not sufficient to obtain enough opened channels to maintain the membrane depolarized. Metabolic causes are due to a gain of function of enzyme activity (deregulated enzymes), except for physical exercise-induced hyperinsulinaemic hypoglycaemia, of still-unknown cause. Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy (Aynsley-Green et al 2000; Cornblath et al 1990; Pagliara et al 1973; Thomas et al 1977). The inappropriate oversecretion of insulin is responsible for profound hypoglycaemia that requires aggressive treatment to prevent severe and irreversible brain damage (Volpe 1995). HI is a heterogeneous disease associated with several genes, various mechanisms of pathogenic mutations and different transmissions (Dunne et al 2004).

Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The 2 subunits of the K(+)(ATP) channel are encoded by either the sulfonylurea receptor gene (SUR1 or ABCC8) or the inward-rectifying potassium channel gene (KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [(18)F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus.

Leptin is a powerful inhibitor of bone formation in vivo . This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and β-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates.

In the last twenty years, blood glucose self-monitoring has attained a nearly optimal level, with reliability, easiness, quickness and safety, which makes it tolerable to a greater number of patients and allows young diabetics to make more easily something which is mandatory to the management of type 1 diabetes. The principles of treatment are identical in children, adolescents and adults. However, many patients experience difficulties in applying the ideal therapeutic model. This must be particularly taken into account in children, who are in a stage of full intellectual and psychological development. Inappropriate demands can drive them to failure and go against the main objective at this period of life, which is education. Reference documents help pediatricians to the daily practice of home blood glucose monitoring and, more generally, management of childhood diabetes: ISPAD Consensus Guidelines (ISPAD=International Society for Pediatric and Adolescent Diabetes), which has been translated in French, and Cahiers de l'AJD (AJD Note books), for educating new patients. Blood glucose monitoring is recommended: to evaluate the glycemic response to the effect of insulin; to confirm hypoglycemia; to prevent hyperglycemia in case of disease; in case of physical exercise. The frequency of home blood glucose monitoring should be individualized, depending on the acceptability for the young patients and the insulin therapeutic regimen.

Objectif Comparer le developpement pubertaire, la prevalence de l’hirsutisme et des anomalies du cycle menstruel et le profil hormonal d’adolescentes diabetiques de type 1 (DID) et d’adolescentes obeses. Patients et methodes Les donnees cliniques et biologiques ont ete recueillies chez 78 patientes DID et 96 patientes obeses âgees de 11,9 ans a 17,9 ans et ayant un stade pubertaire Tanner 4 ou 5. Resultats On retrouve une augmentation de la prevalence de l’hirsutisme et des troubles de regles chez les patientes DID (21 % et 44 % respectivement) et chez les patientes obeses (36,5 % et 42 % respectivement). L’âge de la pubarche, thelarche et de la menarche est plus tardif chez les patientes DID compare aux patientes obeses. L’hirsutisme chez les patientes DID comme les patientes obeses est lie a une hyperandrogenie biologique avec une augmentation de la fraction libre calculee de la testosterone. Cette augmentation du taux libre de testosterone est liee a une elevation des taux de testosterone totale chez les adolescentes DID, alors qu’elle est due a une diminution du taux de la SHBG (Sex Hormone Binding Globulin) chez les adolescentes obeses. Chez les patientes DID, le taux de testosterone libre est correle positivement au taux d’hbA1c. Les anomalies du cycle menstruel sont associees a une hyperandrogenie biologique uniquement chez les patientes DID Conclusion L’hirsutisme et les troubles des regles sont frequents chez les adolescentes DID et les adolescentes obeses. Malgre une hyperandrogenie presente dans les 2 groupes de patientes, le profil hormonal de chacun differe. En effet l’hyperandrogenie chez les patientes DID est liee a une augmentation de la secretion d’androgenes alors que celle-ci est essentiellement due a une diminution de la SHBG chez les patientes obeses. L’origine de l’insuline, exogene chez les patientes DID, endogene chez les patientes obeses pourrait expliquer cette difference hormonale.

Neonatal diabetes (ND) is a rare entity with an estimated incidence of 1/400 000 births in Europe. Hyperglycaemia usually occurs in the first few days of life and patients require insulin treatment. Intrauterine growth retardation, low birth weight, and decreased adipose tissue are frequently associated. ND is permanent in some patients (permanent ND), and in other cases hyperglycaemia is transient (transient ND, OMIM 601410). Type 2 diabetes (T2D) frequently arises in adolescence or adulthood in transient ND patients.1 Chromosome 6 abnormalities are specifically associated with transient ND,2–4 with imprinting effects unmasked by uniparental disomy (UPD) of paternal chromosome 6 and duplications in 6q24.5–7 Two imprinted genes expressed from the paternal allele in various tissues, ZAC/PLAGL1 (zinc finger, apoptosis, cell cycle/pleomorphic adenoma of the salivary gland gene like 1) and HYMAI (hydatidiform mole associated and imprinted transcript), lie in the transient ND locus in 6q24.7, 8 The genetic causes of permanent ND forms are less known. Homozygous mutation in the glucokinase gene ( GK )9 and in the insulin promoter factor-1 (IPF1 ) gene10 may lead to permanent ND owing to complete deficiency of the GK or IPF1 gene product. Mutations of the eukaryotic translation initiation factor-2-alpha kinase 3 ( EIF2AK3) gene were found to segregate with the Wolcott-Rallison syndrome (Omim 226980), a rare autosomal recessive disorder with early onset permanent diabetes mellitus and multiple epiphyseal dysplasia (spondyloepiphyseal dysplasia).11 Clinical information and a molecular genetic study of 14 patients with transient or permanent ND forms are reported. The phenotypes of ND patients from previous reports together with cases reported here provide an initial outline for further studies and molecular mechanisms. Fourteen patients with ND were studied. Their main clinical features are summarised in table 1. The patients were all born at term, mean birth …

Evaluate the correlation between psychopathological disorders in type 1 insulin-dependent diabetic (IDD) children and adolescents and the occurrence of micro-angiopathic complications.Two hundred and five IDD children (104 girls and 101 boys with a mean age of 13.4 +/- 3.5 years on inclusion) were longitudinally monitored between 1994 and 2000. Somatic complications were systematically searched for during a yearly control visit to the day hospital. Psychiatric disorders had been assessed initially by self-administered questionnaires filled-in by the children (Spielberger's STAIC-Trait for anxiety, CESD for depression and Child-EAT for eating habits), by the parents (CBCL, CPRS or GHQ-28) or the principle teachers (CTRS) and diagnostic screening of psychopathological disorders every year.More than 140% of the IDD children (n = 86) were diagnosed DSM-IV, with predominant anxiety (n = 41), during the longitudinal evaluation. Positive screening was significantly associated with higher psychopathological scores before inclusion in the study, with children considered more perturbed by the parents, teachers and the children themselves and mothers who considered themselves more perturbed (GHQ-28 mean 5.6 +/- 7.5 vs. 3.5 +/- 4.8; t = 2.211 p = 0.028). These children were less compliant. Disorders were associated with metabolic imbalance, measured by HbA1c, overweight and an excess of micro-angiopathic, particularly retinopathic, complications.Our results show the frequency of mental disorders in IDD children, the importance of the parents' psychopathology and its association with increased somatic risk. The nature of this relationship requires clarification and the incidence of prevention measures targeted on the psychological problems. The interest of associating a paedopsychiatric element in the therapeutic management of these patients and their families is emphasized.

The purpose of this study was to evaluate the type and frequency of psychopathological disorders observed in obese children and adolescents. We also looked for a correlation between psychic disorders in the obese children, the degree of obesity and paternal psychopathology.The study group included 84 obese children and adolescents aged 5 to 16 years (mean age 10.9 +/- 2.8 years). There were 55 girls and 29 boys. The z-score expressing deviation from the ideal body mass index (IMC) varied from +2 to +10.6 (mean 4 + 1.9). Psychopathological disorders observed in these obese patients were compared in children and adolescents with insulin-dependent diabetes mellitus. The standard diagnostic interview (K-SADS PL) and self-administered questionnaires (Sielberger STAIC-Trait for anxiety and CDI for depression in children or CBCL or GHQ for their parents) were also used to evaluate psychic disorders.More than half of the obese children (47 out of 84) had a DSM-IV diagnosis, often involving anxiety (n = 28). The rate of internalized and externalized psychopathological disorders (measured by STAIC-Trait and CBCL) was higher in the obese children than in the diabetics. The children's psychopathological disorders were more marked if their parents were perturbed, particularly when their mother had an internalized disorder. No correlation was found between the degree obesity and psychopathological disorders in the obese children and adolescents.Our findings show the frequency of mental disorders in obese children and point out the importance of parental psychopathology. This underlines the usefulness of a pedopsychiatric approach implicating the entire family for therapeutic management of these patients.